Programmable Biomolecule-Mediated Processors

Abstract

Programmable biomolecule-mediated computing is a new computing paradigm as compared to contemporary electronic computing. It employs nucleic acids and analogous biomolecular structures as information-storing and -processing substrates to tackle computational problems. It is of great significance to investigate the various issues of programmable biomolecule-mediated processors that are capable of automatically processing, storing, and displaying information. This Perspective provides several conceptual designs of programmable biomolecule-mediated processors and provides some insights into potential future research directions for programmable biomolecule-mediated processors.

Figure 1

Hamiltonian problem solution with the DNA reaction. (A) This Hamiltonian problem has multiple nodes (1–7) and defined directed paths (arrows). The solution is to find a path that starts at node 0 and ends at node 6, while visiting each node only once. Unique DNA sequences of 20 bases are assigned to nodes and defined paths. (B) A sequence of paths must be the unique reverse complement of the two nodes it connects in the Hamiltonian problem. All node and path sequences are added to a polymerase chain reaction mixture for hybridization of path and node DNA molecules. (C) The solution to the path problem is contained in a DNA strand of length 140 bases (seven nodes of 20 bases each). (D) Restriction enzymes can be used to cleave DNA strands at specific sequences to define the start and end points (boundaries) of a path. If the desired path starts at node 1 and ends at node 4, the restriction enzymes can be used to cleave at the sequence of [path 0 > 1 and node 1] and [node 4 and path 4 > 5].

Figure 2

(A) DNA assembly with four single-stranded ends for hybridization to other tiles. DNA ends are designed to be specific. Four-sided DNA assembly can be represented as a Wang tile. Each side of the Wang tile is color-coded, and only matching colors fit together, representing the specificity of DNA single-strand end-binding. (B) Truth table for exclusive disjunction (XOR) logic. (C) Seven Wang tiles with specific color combinations are needed to emulate XOR logic. (D) The Wang tile assembly performed an XOR logic computation. X tiles are inputs, and Y tiles are assembled accordingly. The assembly process starts with the bottom left root tile. X₁ tile of “1” is introduced. If the first Y₀ tile is a “1”, the Wang tile rule dictates that only a Y tile of “0” can be assembled to match the color. Hence, Y₁ is “0” according to the logic table. Logic computation is cascading as [Y_(i-1) XOR X_i=Y_i]. The next computation is Y₁ XOR X₂=Y₂.

Figure 3

(A) Cascading DNA strand displacement (DSD) logic gates: Each single-stranded DNA (ssDNA) input requires a DSD unit that acts as a logic gate, ready to accept the input toehold and release the reporter strand to form the next logic gate for subsequent inputs. The input 2 stage requires the input 1 reporter to signal the completion of the input 1 detection in preparation for the input 2 toehold. By designing more stages to form a cascading repeat circuit, the circuit can accept multiple inputs. (B) Multi-input DSD logic gate: For the same logic operation, only a single assembly of double-stranded DNA with a toehold region corresponding to the ssDNA input is required. Since intermediate reporting strand is eliminated, fewer unique toehold sequences are required, and therefore a simpler toehold design. Multi-input DSD logic gates generate less DNA waste than cascading DSD. (C) The wasted DNA byproducts of DSD can create unwanted pathways, releasing intermediate signals or output reporters. Multi-input DSD produces less waste DNA than cascading DSD.

Figure 4

DNA strand displacement (DSD) used to emulate conjunction (AND) logic. AND logic outputs a positive signal when both input 1 AND input 2 are present. 1: DNA assembly with two toehold regions for two inputs, respectively. 2: The first input single-strand DNA (ssDNA) emerges and attaches to toehold region 1 (blue). 3: The DSD process occurs and displaces excess ssDNA, revealing toehold region 2 (red). 4: Input 2 ssDNA binds to revealed toehold region 2 and initiates DSD process. 5: After complete displacement by input 2 ssDNA, the final excess ssDNA (green) is the result of input 1 AND input 2 ssDNA. Overall process emulates AND where only in the presence of input 1 and 2 ssDNA is output ssDNA released.

Figure 5

Overview of DNA-mediated computing. Each method (deoxyribonuclease, tiling, and DNA strand displacement (DSD)) may be restricted to a limited input, computing (path problem, logic, or artificial neural network (ANN)), and output. Input and output combined form the interface of a method. For DSD, input may be synthetic or natural (cancer miRNAs and viral RNA). The DSD computing task can be directed to logic gates or ANNs and lead to either a small-molecule release or DNA/RNA release.